Lung cancer remains the leading cause of cancer death in the world for both men and women, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer. Nearly 80% of lung cancer is diagnosed at an advanced inoperable stage, and current systemic therapy offers only modest benefits for lung cancer patients. In addition, the development of malignant tumors is in part characterized by the ability of a tumor cell to overcome cell-cell adhesion and to invade surrounding tissue. In general, it is not the primary tumor, but metastasis from the primary tumor that is responsible for the demise of most lung cancer patients. EMT has been associated with the early onset of cancer. The essential feature of EMT are disruption of intercellular contacts and the enhancement of cell motility, which leads to the release of cells from parental epithelial tissue making these cells more suitable for migration and invasion to neighboring cells (e.g. tumor invasion and dissemination). The overall goal of this study is to determine the role of b-catenin independent (i.e. non- canonical) Wnt signaling on EMT and metastasis in NSCLC. Our findings to date suggest that Wnt 7a functions: 1) as a tumor suppressor in normal lung epithelia, and 2) that activation of Wnt 7a activates b- catenin independent (non-canonical) Wnt signaling through Fzd9, inducing activation of the tumor suppressor gene PPARg. In previous work, we have demonstrated that Wnt 7a and/or Fzd 9 expression is frequently reduced in NSCLC, and that the loss of Wnt 7a and/or Fzd 9 is strongly associated with epithelial to mesenchymal transition (EMT), loss of cellular polarity, and increased susceptibility to lung carcinogenesis in mice. Based on these findings, we hypothesize that Wnt 7a/Fzd9 signaling plays a novel role in establishing cell polarity (i.e. inducing MET), and reducing tumor metastasis in the lung by regulating non-canonical Wnt (b- catenin independent) signaling. Moreover, our recent finding of frequent promoter methylation of Wnt 7a in human lung cancer makes Wnt 7a a potentially attractive future therapeutic target in the treatment of NSCLC. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death for both men and women in the United States. In fact, more deaths will occur this year due to lung cancer than breast, prostate, and colorectal cancers combined. The experimental strategies outlined in this project are designed to evaluate the contribution of the non-canonical Wnt pathway to lung cancer and to identify genetic targets of this pathway that could be used to develop potential small molecular therapeutic targets for the treatment of lung cancer.